N-[2-4-(1H-Imidazol-1-yl)alkyl]-arylamides and pharmaceutical compositions

ABSTRACT

This disclosure describes novel N-[ω-(1H-imidazol-1-yl)alkyl]arylamides which possess the property of inhibiting the enzyme thromboxane synthetase and are also useful in the treatment of hypertension and myocardial ischemia.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of our copending applicationSer. No. 470,112, filed Feb. 28, 1983 now abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and, more particularly,is concerned with novel N-[ω-(1H-imidazol-1-yl)alkyl]arylamides whichmay be represented by the following structural formula: ##STR1## whereinA is a divalent moiety of the formulae: ##STR2## wherein n is an integerfrom 2 to 8, inclusive, ARYL is 1-naphthyl, 2-naphthyl, diphenylmethyl,9-fluorenyl or a moiety of the formula: ##STR3## wherein R₁, R₂ and R₃are each individually selected from the group consisting of hydrogen,halogen, trifluoromethyl, cyano, carboxy, amino, alkyl having from oneto four carbon atoms, alkoxy having from one to four carbon atoms,benzylamino, allylamino, alkylamino having from one to three carbonatoms, dialkylamino having from one to three carbon atoms in each alkylgroup, alkythio having from one to three carbon atoms, alkylsulfonylhaving from one to three carbon atoms, acetyl, acetamido, phenyl andbenzoyl; Q is a divalent moiety of the formulae: ##STR4## wherein m iszero, 1, 2 or 3; R₄ is hydrogen, alkyl having from one to three carbonatoms or benzyl; and R₅ and R₆ are each individually selected from thegroup consisting of hydrogen, phenyl and alkyl having from one to threecarbon atoms. A preferred embodiment of the present invention may berepresented by the following structural formula: ##STR5## wherein R₁,R₂, R₃, n, R₅ and R₆ are as hereinabove defined.

The organic bases of this invention form non-toxic acid-addition saltswith a variety of pharmacologically acceptable organic and inorganicsalt-forming reagents. Thus, acid-addition salts, formed by admixture ofthe organic free base with one or more equivalents of an acid, suitablyin a neutral solvent, are formed with such acids as sulfuric,phosphoric, hydrochloric, hydrobromic, maleic, sulfamic, citric, lactic,malic, succinic, tartaric, acetic, benzoic, fumaric, gluconic, ascorbic,and the like. For purposes of this invention the free bases areequivalent to their non-toxic acid-addition salts. The acid-additionsalts of the organic bases of the present invention are, in general,crystalline solids, relatively soluble in water, methanol and ethanolbut relatively insoluble in non-polar organic solvents such as diethylether, benzene, toluene, and the like.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention may be readily prepared asset forth in the following reaction schemes wherein ARYL, Q, R₄, A, R₅and R₆ are as hereinabove defined; R₇ is hydrogen, alkyl having from oneto 3 carbon atoms, allyl or benzyl; R₈ is benzyl or alkyl having fromone to three carbon atoms; and X is chloro, bromo or moiety of theformula: ##STR6## wherein ARYL and Q are as hereinabove defined and theresulting anhydride is symmetrical. ##STR7##

In accordance with Method I, an appropriately substituted acid (I) isreacted with 1,1'-carbonyldiimidazole in an inert solvent such asdioxane, dimethyllformamide or tetrahydrofuran at ambient temperaturesfor 1-3 hours to provide the intermediates (2). Treatment of theintermediates (2) with an appropriately substituted1H-imidazole-1-alkanamine (3), either as the free base or a saltthereof, provides the final products (4). The final condensation of(2)+(3) is best carried out by merely adding (3) to the reaction mixturefor 1-5 hours. Concentration of the reaction mixture followed by theaddition of aqueous base (KOH or NaOH) in a solvent such as CHCl₃ orCCl₄ and isolation from the organic phase provides the products (4) asthe free bases. ##STR8##

In accordance with Method II, an appropriately substituted acid halideor acid anhydride (5) is condensed with an appropriately substituted1H-imidazole-1-alkanamine (3), either as the free base or a saltthereof, to provide the final products (4). This condensation is bestcarried out at ambient temperatures for up to 18 hours in an inertsolvent such as CH₂ Cl₂, CHCl₃ or CCl₄ and in the presence of an acidacceptor such as aqueous base (2N KOH or 2N NaOH), soda ash orconcentrated (12%) aqueous ammonia. The resulting organic phase is thenwashed with water, dried, and concentrated to give the crystallineproducts (4) as the free bases. ##STR9##

In accordance with Method III, an appropriately substituted isatoicanhydride (6) is condensed with an appropriately substituted1H-imidazole-1-alkanamine (3) to provide the corresponding substituted2-amino-N-[ω-(1H-imidazol-1-yl)alkyl]benzamides (7). This condensationis readily carried out in an inert solvent such as benzene, toluene,ethanol or dimethylsulfoxide at the reflux temperature thereof for aperiod of 15 minutes to an hour or so. The product (7) precipitates fromthe reaction mixture and is collected by filtration and purified.##STR10##

In accordance with Method IV, an appropriately substitutedN-[ω-(1H-imidazol-1-yl)alkyl]arylamide (8) is treated with sodiumhydride in an inert solvent such as dioxane, dimethylformamide ortetrahydrofuran at ambient temperatures for 1-3 hours to form theintermediate sodium salt in situ. Addition to the reaction mixture of analkyl halide of the formula: R₈ --Hal (wherein Hal is chloro, bromo oriodo), followed by stirring at ambient temperatures for 12-24 hoursprovides the alkylated derivative (9). Isolation of (9) is readilyaccomplished by concentration of the reaction mixture, dilution withwater, and extraction into a water insoluble solvent such as CH₂ Cl₂,CHCl₃ or CCl₄. ##STR11##

In accordance with Method V, an appropriately substitutednitro-N-[ω-(1H-imidazol-1-yl)alkyl]arylamide (10) is reduced bycatalytic hydrogenation to the corresponding amino derivative (11) in aParr apparatus at a few atmospheres pressure of hydrogen in the presenceof a catalyst such as Raney nickel, palladium or carbon, and the like.##STR12##

In accordance with Method VI, an appropriately substituted phthalicanhydride (12) is condensed with an appropriately substituted1H-imidazole-1-alkanamine (3) to provide the corresponding substituted2-carboxy-N-[ω-(1H-imidazol-1-yl)alkyl]benzamides (13). Thiscondensation is readily carried out in an inert solvent such asmethylene chloride or chloroform at room temperature for a few hours.

This invention also pertains to novel substitutedN-[ω-(1H-imidazol-1-yl)alkyl]phthalimides which may be represented bythe following structural formula: ##STR13## wherein p is an integer fromthree to ten, inclusive, R₅ and R₆ are as hereinbefore defined, and R₉and R₁₀ are each individually selected from the group consisting ofhydrogen, halogen, alkyl having from one to three carbon atoms, nitroand amino with the proviso that R₉ and R₁₀ may not both be hydrogen whenp is three. These phthlaimide derivatives are intermediates for thepreparation of the 1H-imidazole-1-alkanamines (3) wherein R₄ ishydrogen. They also possess the property of inhibiting the enzymethromboxane synthetase and are also useful in the treatment ofhypertension. These novel phthalimide derivatives may be readilyprepared as set forth in the following reaction schemes wherein p, R₅,R₆, R₉ and R₁₀ are as hereinbefore defined and X is chloro, bromo oriodo. ##STR14##

In accordance with Method A, an appropriately substituted phthalimide(14) (as the potassium salt) is condensed with an appropriatelysubstituted N-haloalkyl-imidazole (15) to provide the final products(16). This condensation is best carried out in an inert solvent such asdioxane, dimethylformamide or tetrahydrofuran at 30°-100° C. for up to18 hours. ##STR15##

In accordance with Method B, the appropriately substituted imidazole(18) is first converted to a salt form with silver nitrate, sodiumhydride, and the like and then condensed with an appropriatelysubstituted N-haloalkylphthalimide (17) to provide the products (16).The salt formation and subsequent condensation are best carried out inan inert solvent such as dimethylformamide or methylethyl ketone at30°-100° C. for up to 18 hours. ##STR16##

In accordance with Method C, an appropriately substituted phthalimide(14) or phthalic anhydride (19) is condensed with an appropriatelysubstituted N-aminoalkylimidazole (20) to provide the products (16).Although this condensation may be carried out in a high boiling inertsolvent at 140°-180° C. for several hours, it is most convenientlycarried out neat as a simple fusion reaction.

The compounds of this invention inhibit thromboxane synthetase enzymewithout interfering with other enzymes in the arachadonic acid cascade.Thus, these compounds are useful in the treatment of diseasescharacterized by an imbalance of thromboxane A₂ /prostacyclin such asischemic heart disease, transient ischemic attack, thrombosis andmigraine. Recent reviews have established the role of thethromboxane/prostacyclin balance in the vascular system [CardiovascularDiseases: New Trends in Surgical and Medical Aspects, H. Barnett, P.Paoletti, E. Flamm and G. Brambilla, eds., Elsevier/North-HollandBiomedical Press, pp 137-150 (1981)]. Prostacyclin (PGI₂) is a potentvasodilator and platelet aggregation inhibitor, whereas thromboxane(TWA₂) is a powerful vasoconstrictor and causative of plateletaggregation. TXA₂ is synthesized by thromboxane synthetase enzymelocated in, for example, blood platelets. When TXA₂ production isincreased relative to PGI₂, platelet aggregation, thrombosis andvasopasm may occur [Lancet (i), 1216 (1977); Lancet, 479 (1977);Science, 1135 (1976); Amer. J. Cardiology, 41, 787 (1978)]. TXA₂synthetase inhibitors have been shown to have superior anti-thromboticaction to that of aspirin [J. Clin. Invest., 65, 400 (1980); Br. J.Pharmac., 76, 3 (1982)].

The role of prostaglandins including TXA₂ and PGI₂ in ischemic heartpatients has been reviewed [Cardiovascular Pharmacology of theProstaglandins, A. G. Herman, P. M. Vanhoute, H. Denolin and A. Goosens,eds., Raven Press, New York, pp 361-374 (1982)]. Injection of TXA₂ intocoronary arteries of guinea pigs and rabbits causes myocardial ischemiaand subendocardial necrosis [Drugs of the Future, 7, 331 (1982); Proc.Jap. Acad., 53(B), 38 (1977); Eur. J. Pharmacol., 53 49(1978)]. Recentresearch has demonstrated the beneficial effects of PGI₂ and selectiveinhibition of thromboxane synthetase on ischemic myocardium in canines[J. Cardiovascular Pharmacology, 4, 129 (1982]. Thus compounds whichselectively inhibit thromboxane synthetase (and hence TXA₂) withoutadversely affecting PGI₂ are useful in the treatment of vasculardiseases such as ischemia and migraine. In addition, inhibition of TXA₂formation may effectively treat platelet aggregation and preventthrombosis.

Under urethan anesthesia, 10 μl of arterial blood was collected in oneml. of 3.2% sodium citrate in a polystyrene tube from Okamoto-Aokispontaneously hypertensive rats (SHR) (Taconic Farms, Germantown, NY)between 19 and 24 weeks in age. The blood was diluted with 3 ml. coldsaline and centrifuged at room temperature for 15 minutes at 460×g. Theplatelet rich plasma (PRP) was separated. The platelets were isolated bycentrifuging the PRP for 10 minutes at 1060×g and were washed in 4 ml.cold oxygenated Krebs phosphate buffer, pH 7.4. The chilled pateletsrecovered from centrifuging at 800×g for 10 minutes were resuspended inoxygenated Krebs phosphate buffer and diluted to contain 4.5-6.0×10⁴platelets/μl.

The inhibition of thromboxane (TX) formation was studied by determiningthe condensation of thromboxane B₂ (TXB₂), the stable hydrolysis productof TXA₂. Assay samples, prepared on ice, contained 200 μl plateletsuspension, 50 μl saline, and 50 μl vehicle or drug under study(OKY-1581, UK-37248-01, 1-benzylimidazole, or indomethacin). The sampleswere incubated for 10 minutes at 37° C. in a metabolic shaker. Thereaction was terminated by immersing the tubes in an ice bath and adding50 μl of 0.5M citric acid. The samples were centrifuged for 10 minutesin a refrigerated centrifuge and the supernatants thus obtained weredecanted and stored at -20° C. The TXB₂ content for each sample wasdetermined by a direct radioimmunoassay (RIA) utilizing a TXB₂ specificRIA kit purchased from New England Nuclear, Boston, MA and expressed aspg TXB₂ formed minute⁻¹ sample⁻¹, from which the percent inhibition ofTXB₂ formation was calculated. The results of this test onrepresentative compounds of this invention appear in Table I below.

                  TABLE I                                                         ______________________________________                                        Product               Dose   % Inhibition                                     ______________________________________                                        3,4-dichloro-N--[3-(1H--imidazol-1-yl)-                                                             10.sup.-4                                                                            92.7                                             propyl]benzamide                                                              3,4-dichloro-N--[2-(1H--imidazol-1-yl)-                                                             10.sup.-4                                                                            58.5                                             ethyl]benzamide                                                               4-fluoro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            87.1                                             propyl]benzamide                                                              N--[3-(1H--imidazol-1-yl)propyl]benza-                                                              10.sup.-4                                                                            96.3                                             mide                                                                          3-trifluoromethyl-N--[3-(1H--imidazol-1-                                                            10.sup.-4                                                                            84                                               yl)propyl]benzamide                                                           N--[3-(1H--imidazol-1-yl)propyl]-9H--                                                               10.sup.-4                                                                            100                                              fluorene-9-carboxamide                                                        N--[3-(1H--imidazol-1-yl)propyl]-2-naph-                                                            10.sup.-4                                                                            97                                               thalenecarboxamide                                                            2-chloro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            99.7                                             propyl]benzamide                                                              2-fluoro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            83.9                                             propyl]benzamide                                                              4-chloro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            95                                               propyl]benzamide                                                              3-chloro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            75.4                                             propyl]benzamide                                                              3-fluoro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            95.8                                             propyl]benzamide                                                              N--[3-(1H--imidazol-1-yl)propyl]-4-                                                                 10.sup.-4                                                                            83.2                                             methylbenzamide                                                               4-bromo-N--[3-(1H--imidazol-1-yl)-                                                                  10.sup.-4                                                                            85                                               propyl]benzamide                                                              4-acetyl-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            89.5                                             propyl]benzamide                                                              4-fluoro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            53.1                                             propyl]benzeneacetamide, fumarate                                             N--[3-(1H--imidazol-1-yl)propyl]-α-oxo                                                        10.sup.-4                                                                            79.7                                             benzeneacetamide, fumarate                                                    N--[3-(1H--imidazol-1-yl)propyl]-2-                                                                 10.sup.-4                                                                            86.2                                             phenoxyacetamide                                                              4-benzoyl-N--[3-(1H--imidazol-1-yl)-                                                                10.sup.- 4                                                                           103.4                                            propyl]benzamide                                                              N--[3-(1H--imidazol-1-yl)propyl]-1-naph-                                                            10.sup.-4                                                                            75                                               thalenecarboxamide                                                            4-chloro-N--[3-(4-phenyl-1H--imidazol-1-                                                            10.sup.-4                                                                            69                                               yl)propyl]benzamide                                                           N--[3-(1H--imidazol-1-yl)propyl][1,1'-                                                              10.sup.-4                                                                            105.7                                            biphenyl]-4-carboxamide                                                       N--[3-(1H--imidazol-1-yl)propyl]-3,4,5-                                                             10.sup.-4                                                                            100.9                                            trimethoxybenzamide                                                           4-(acetylamino)-N--[3-(1H--imidazol-1-                                                              10.sup.-4                                                                            98.7                                             yl)propyl]benzamide                                                           2-(4-chlorophenoxy)-N--[3-(1H--imidazol-                                                            10.sup.-4                                                                            84.6                                             1-yl)propyl]acetamide                                                         N--[3-(1H--imidazol-1-yl)propyl]-4-                                                                 10.sup.-4                                                                            88.9                                             methoxybenzamide                                                              N--[3-(1H--imidazol-1-yl)propyl]-4-                                                                 10.sup.-4                                                                            96.7                                             iodobenzamide                                                                 4-cyano-N--[3-(1H--imidazol-1-yl)-                                                                  10.sup.-4                                                                            90.7                                             propyl]benzamide                                                              N--[3-(1H--imidazol-1-yl)propyl]-4-                                                                 10.sup.-4                                                                            101.8                                            (methylthio)-benzamide                                                        N--[3-(1H--imidazol-1-yl)propyl]-4-                                                                 10.sup.-4                                                                            80.1                                             (methylsulfonyl)-benzamide                                                    3,4-dichloro-N--[4-(1H--imidazol-1-yl)-                                                             10.sup.-4                                                                            100                                              butyl]benzamide                                                               N--[3-(1H--imidazol-1-yl)propyl]-4-(di-                                                             10.sup.-4                                                                            93                                               methylamino)benzamide                                                         2-(2,3-dichlorophenoxy)-N--[3-(1H---imid-                                                           10.sup.-4                                                                            100                                              azol-1-yl)propyl]acetamide, fumarate                                          4-bromo-N--[3-(4-phenyl-1H--imidazol-1-                                                             10.sup.-4                                                                            66                                               yl)propyl]benzamide                                                           3-chloro-N--[3-(4-methyl-1H--imidazol-1-                                                            10.sup.-4                                                                            84                                               yl)propyl]benzamide                                                           4-chloro-N--[3-4-methyl-1H--imidazol-1-                                                             10.sup.-4                                                                            93                                               yl)propyl]benzamide                                                           3-bromo-N--[3-(4-methyl-1H--imidazol-1-                                                             10.sup.-4                                                                            93                                               yl)propyl]benzamide                                                           4-bromo-N--[3-(4-methyl-1H--imidazol-                                                               10.sup.-4                                                                            80                                               1-yl)propyl] benzamide                                                        4-iodo-N--[3-(4-methyl-1H--imidazol-                                                                10.sup.-4                                                                            99                                               1-yl)propyl]benzamide                                                         3,4-dichloro-N--[3-(4-methyl-1H--imi-                                                               10.sup.-4                                                                            90                                               dazol-1-yl)propyl]benzamide                                                   4-trifluoromethyl-N--[3-(4-methyl-                                                                  10.sup.-4                                                                            92                                               1H--imidazol-1-yl)propyl]benzamide                                            4-methyl-N--[3-(4-methyl-1H--imida-                                                                 10.sup.-4                                                                            76                                               zol-1-yl)propyl]phenylacetamide                                               4-trifluoromethyl-N--[4-(1H--imida-                                                                 10.sup.-4                                                                            97                                               zol-1-yl)butyl]benzamide fumarate                                             N--[4-(1H--imidazol-1-yl)butyl]-1-                                                                  10.sup.-4                                                                            95                                               naphthalenecarboxamide                                                        2-phenyl-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            95                                               propyl]benzamide                                                              N--[3-(1H--imidazol-1-yl)propyl]di-                                                                 10.sup.-4                                                                            84                                               phenylacetamide                                                               2-amino-5-chloro-N--[3-(1H--imidazol-                                                               10.sup.-4                                                                            96                                               1-yl)-propyl]benzamide                                                        2-allylamino-5-chloro-N--[3-(1H--imi-                                                               10.sup.-4                                                                            95                                               dazol-1-yl)propyl]benzamide                                                   2-amino-5-chloro-3-methyl-N--[3-(1H--                                                               10.sup.-4                                                                            80                                               imidazol-1-yl)propyl]benzamide di-                                            hydrochloride                                                                 2-methylamino-N--[3-(1H--imidazol-1-                                                                10.sup.-4                                                                            57                                               yl)-propyl]benzamide                                                          2-[4-(1H--imidazol-1-yl)butyl]-1H--                                                                 10.sup.-4                                                                            99                                               isoindole-1,3(2H)--dione                                                      2-[5-(1H--imidazol-1-yl)pentyl]-1H--                                                                10.sup.-4                                                                            92                                               isoindole-1,3(2H)--dione                                                      2-ethylamino-N--[3-(1H--imidazol-1-                                                                 10.sup.-4                                                                            86                                               yl)propyl]benzamide                                                           4-chloro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            100                                              2-methylpropyl]benzamide                                                      fumarate                                                                      3-chloro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            93                                               butyl]benzamide                                                               3,4-dichloro-N--[3-(1H--imidazol-1-                                                                 10.sup.-4                                                                            86                                               yl)butyl]benzamide                                                            4-bromo-N--[3-(1H--imidazol-1-yl)-                                                                  10.sup.-4                                                                            91                                               butyl]benzamide                                                               4-chloro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.- 4                                                                           96                                               butyl]benzamide                                                               4-chloro-N--[3-(1H--imidazol-1-yl)-                                                                 10.sup.-4                                                                            100                                              1-phenylpropyl]benzamide                                                      4-bromo-N--[3-(1H--imidazol-1-yl)-                                                                  10.sup.-4                                                                            100                                              1-phenylpropyl]benzamide                                                      ______________________________________                                    

The novel compounds of the present invention are also active hypotensiveagents and were tested for hypotensive activity by the method of P. S.Chan and D. Poorvin, Clinical and Experimental Hypertension, 1 (6),817-830 (1979). Male, 16 week old, spontaneously hypertensive rats ofthe Okamoto strain, from Taconic Farms, Germantown, N.Y. having anaverage mean arterial blood pressure of 160±1.5 mm of mercury are usedin the test. One to 3 rats are used per test compound. A rat is dosed bygavage with a test compound, suspended in 2% pre-boiled starch at aconcentration of 50 mg/ml, at a dose of 100 mg/kg of body weight orless, with 0.9% sodium chloride loading at a dose of 25 ml/kg of bodyweight. A second identical dose of the test compound, without sodiumchloride loading is given 24 hours later. At 28 hours after the initialdose, the mean arterial blood pressure (MABP) is measured by the methodof Chan and Poorvin vide supra. The procedure is repeated in a secondand third rat when necessary. Based on the data obtained and using thethree-stage "sequential probability ratio test" statistical method, thecriteria for activity or retest are as follows:

If the blood pressure in the first rat is ≦116 mm mercury the compoundis considered active. If the blood pressure is between 117 and 146 mm, asecond rat is used. If the average blood pressure of the first andsecond rats is ≦122 mm the compound is considered active. If the averageblood pressure is between 123 and 137 mm, a third rat is used. If theaverage blood pressure of the three rats is ≦128 mm the compound isconsidered active. The results of this test on representative compoundsof the present invention appear in Table II below.

                  TABLE II                                                        ______________________________________                                                                MABP/mm Hg                                            Compound                (no. of rats)                                         ______________________________________                                        N--[3-(1H--imidazol-1-yl)propyl]benzamide                                                             128                                                                           (3)                                                   4-chloro-N--[3-(1H--imidazol-1-yl)propyl]-                                                            126                                                   benzamide               (3)                                                   3-chloro-N--[3-(1H--imidazol-1-yl)propyl]-                                                            124                                                   benzamide               (3)                                                   4-bromo-N--[3-(1H--imidazol-1-yl)propyl]-                                                             120                                                   benzamide               (3)                                                   4-bromo-N--[3-(4-methyl-1H--imidazol-1-yl)-                                                           122                                                   propyl]benzamide        (3)                                                   3,4-dichloro-N--[3-(4-methyl-1H--imidazol-                                                            116                                                   1-yl)propyl]benzamide   (2)                                                   N--[3-(1H--imidazol-1-yl)propyl]-4-methyl-                                                            109                                                   benzeneacetamide, hemifumarate                                                                        (2)                                                   4-bromo-N--[3-(2-phenyl-1H--imidazol-1-yl)-                                                           115                                                   propyl]benzamide, fumarate                                                                            (2)                                                   N--[3-(1H--imidazol-1-yl)propyl]-2-naphtha-                                                           127                                                   lenecarboxamide         (4)                                                   N--[3-(1H--imidazol-1-yl)propyl]-1-naphtha-                                                           124                                                   lenecarboxamide         (3)                                                   4-chloro-N--[3-(4-phenyl-1H--imidazol-1-yl)-                                                          125                                                   propyl]benzamide        (3)                                                   4-chloro-N--[3-(2-methyl-1H--imidazol-1-yl)-                                                          121                                                   propyl]benzamide        (2)                                                   2-[4-(1H--imidazol-1-yl)butyl]-1H--isoindole-                                                         120                                                   1,3(2H)--dione          (2)                                                   2-[6-(1H--imidazol-1-yl)hexyl]-1H--isoindole-                                                         110                                                   1,3(2H)--dione          (1)                                                   2-[3-(1H--imidazol-1-yl)butyl]-1H--isoindole-                                                         124                                                   1,3(2H)--dione          (3)                                                   3-chloro-N--[3-(4-methyl-1H--imidazol-1-                                                              122                                                   yl)propyl]benzamide     (3)                                                   4-chloro-N--[3-(4-methyl-1H--imidazol-1-                                                              112                                                   yl)propyl]benzamide     (2)                                                   3,4-dichloro-N--[3-(4-methyl-1H--imidazol-                                                            116                                                   1-yl)propyl]benzamide   (2)                                                   4-trifluoromethyl-N--[3-(4-methyl-1H--                                                                114                                                   imidazol-1-yl)propyl]benzamide                                                                        (2)                                                   4-trifluoromethyl-N--[4-1H--imidazol-1-yl)                                                            123                                                   butyl]benzamide fumarate                                                                              (3)                                                   2-phenyl-N--[3-(1H--imidazol-1-yl)propyl]-                                                            124                                                   benzamide               (3)                                                   2-amino-5-chloro-N--[3-(1H--imidazol-1-                                                               113                                                   yl)propyl]benzamide     (1)                                                   2-allylamino-5-chloro-N--[3-(1H-- imidazol-                                                           124                                                   1-yl)propyl]benzamide   (3)                                                   2-amino-5-chloro-3-methyl-N--[3-(1H--imi-                                                             125                                                   dazol-1-yl)propyl]benzamide dihydro-                                                                  (3)                                                   chloride                                                                      3,4-dichoro-N--[3-(1H--imidazol-1-yl)-                                                                123                                                   butyl]benzamide         (3)                                                   ______________________________________                                    

The novel compounds of the present invention have been found to behighly useful for inhibiting thromboxane synthetase in mammals whenadministered in amounts ranging from about 0.1 mg to about 20.0 mg/kg ofbody weight per day. A preferred dosage regimen for optimum resultswould be from about 0.5 mg to about 10.0 mg/kg of body weight per day.Such dosage units are employed that a total of from about 35 to about700 mg of active compound for a subject of about 70 kg of body weightare administered in a 24 hour period. This dosage regimen may beadjusted to provide the optimum therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. The compounds of this invention are preferably administeredorally but may be administered in any convenient manner such as by theintravenous, intramuscular, or subcutaneous routes.

Compositions according to the present invention having the desiredclarity, stability and adaptability for parenteral use are obtained bydissolving from 0.10% to 10.0% by weight of active compound in a vehicleconsisting of a polyhydric aliphatic alcohol or mixtures thereof.Especially satisfactory are glycerin, propylene glycol, and polyethyleneglycols. The polyethylene glycols consist of a mixture of non-volatile,normally liquid, polyethylene glycols which are soluble in both waterand organic liquids and which have molecular weight of from about 200 to1500. Although the amount of active compound dissolved in the abovevehicle may vary from 0.10% to 10.0% by weight, it is preferred that theamount of active compound employed be from about 3.0 to about 9.0% byweight. Although various mixtures of the aforementioned non-volatilepolyethylene glycols may be employed, it is preferred to use a mixturehaving an average molecular weight of from about 200 to about 400.

In addition to the active compound, the parenteral solutions may alsocontain various preservatives which may be used to prevent bacterial andfungal contamination. The preservatives which may be used for thesepurposes are, for example, myristyl-gamma-picolinium chloride,benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-α-glycerolether, methyl and propyl parabens, and thimerosal. As a practicalmatter, it is also convenient to employ antioxidants. Suitableantioxidants include, for example, sodium bisulfite, sodiummetabisulfite, and sodium formaldehyde sulfoxylate. Generally, fromabout 0.05 to about 0.2% concentrations of antioxidant are employed.

For intramuscular injection, the preferred concentration of activecompound is 0.25 to 0.50 mg/ml of the finished compositions. The novelcompounds of the present invention are equally adapted to intravenousadministration when diluted with water or diluents employed inintravenous therapy such as isotonic glucose in appropriate quantities.For intravenous use, initial concentrations down to about 0.05 to 0.25mg/ml of active ingredient are satisfactory.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds may be incorporated with excipientsand used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and flavoring such as cherry ororange flavor. Of course, any material used in preparing any dosage unitform should be pharmaceutically pure and substantially non-toxic in theamounts employed.

The following specific examples illustrate the preparation of thecompounds of the present invention.

EXAMPLE 1 3-Chloro-N-[3-(1H-imidazol-1-yl)propyl]benzamide

A mixture of 6.0 g. of 1H-imidazole-1-propanamine dihydrochloride, 45ml. of 2N sodium hydroxide and 150 ml. of methylene chloride was stirredat room temperature and 3.9 ml. of 3-chlorobenzoyl chloride was added.The reaction mixture was stirred for 18 hours, then methylene chlorideand 15 ml. of 1N sodium hydroxide were added and the layers wereseparated. The organic layer was washed with water, dried over magnesiumsulfate, and concentrated to remove the solvent. The residue wastriturated with diethyl ether and the crystalline product recovered byfiltration and recrystallized from ethanol, giving the desired product,m.p. 125°-127° C.

Following the procedure of this example and using the appropriatebenzoyl chloride, the products of Examples 2-19 were obtained as setforth in Table III below.

                  TABLE III                                                       ______________________________________                                             Benzoyl                                                                  Ex.  Chloride    Product            m.p.°C.                            ______________________________________                                         2   2-chlorobenzoyl                                                                           2-chloro-N--[3-(1H--imida-                                                                        98-101                                        chloride    zol-1-yl)propyl]benzamide                                     3   4-chlorobenzoyl                                                                           4-chloro-N--[3-(1H--imida-                                                                       141-143                                        chloride    zol-1-yl)propyl]benzamide                                     4   3,4-dichloro-                                                                             3,4-dichloro-N--[3-(1H--imi-                                                                     158-160                                        benzoyl     dazol-1-yl)propyl]benza-                                          chloride    mide                                                          5   2-fluorobenzoyl                                                                           2-fluoro-N--[3-(1H--imida-                                                                       73-75                                          chloride    zol-l-yl)propyl]benzamide                                     6   3-fluorobenzoyl                                                                           3-fluoro-N--[3-(1H--imida-                                                                       136--138                                       chloride    zol-1-yl)propyl]benzamide                                     7   4-fluorobenzoyl                                                                           4-fluoro-N--[3-(1H--imida-                                                                       73-75                                          chloride    zol-1-yl)propyl]benzamide                                     8   3-bromobenzoyl                                                                            3-bromo-N--[3-(1H--imidazol-                                                                     113-115                                        chloride    1-yl)propyl]benzamide                                         9   4-bromobenzoyl                                                                            4-bromo-N--[3-(1H--imidazol-                                                                     156-159                                        chloride    1-yl)propyl]benzamide                                        10   4-trifluoro-                                                                              4-trifluoromethyl-N--[3-                                                                         107-109                                        methylbenzoyl                                                                             (1H--imidazol-1-yl)pro-                                           chloride    pyl]benzamide                                                11   4-methyl-   N--[3-(1H--imidazol-1-yl)-                                                                       107-109                                        benzoyl     propyl]-4-methylbenz-                                             chloride    amide                                                        12   4-cyanobenzoyl                                                                            4-cyano-N--[3-(1H--imidazol-                                                                     154-156                                        chloride    1-yl)propyl]benzamide                                        13   3-nitrobenzoyl                                                                            N--[3-(1H--imidazol-1-yl)-                                                                       124-126                                        chloride    propyl]-3-nitrobenzamide                                     14   4-(1,1-dimethyl-                                                                          N--[3-(1H--imidazol-1-yl)-                                                                       oil                                            ethyl)benzoyl                                                                             propyl]-4-(1,1-dimethyl-                                          chloride    ethyl)benzamide                                              15   3-trifluoro-                                                                              3-trifluoromethyl-N--[3-(1H--                                                                    82-84                                          methylbenzoyl                                                                             imidazol-1-yl)propyl]benz-                                        chloride    amide                                                        16   9-fluorene- N--[3-(1H--imidazol-1-yl)pro-                                                                    164-167                                        carbonyl    pyl]-9H--fluorene-9-carbox-                                       chloride    amide                                                        17   2-naphthoyl N--[3-(1H--imidazol-1-yl)pro-                                                                     99-101                                        chloride    pyl]-2-naphthalenecarboxamide                                18   1-naphthoyl N--[3-(1H--imidazol-1-yl)pro-                                                                    108-110                                        chloride    pyl]-1-naphthalenecarboxamide                                19   2-phenyl-   2-phenyl-N--[3-(1H--imidazol-                                                                    90-92                                          benzoyl     1-yl)propyl]benzamide                                             chloride                                                                 ______________________________________                                    

Following the procedure of Example 1 and using the appropriate benzoylchloride but substituting 1H-imidazole-1-ethanamine dihydrochloride forthe 1H-imidazole-1-propanamine dihydrochloride of that example, theproducts of Examples 20 and 21 were obtained as set forth in Table IVbelow.

                  TABLE IV                                                        ______________________________________                                        Ex.  Benzoyl Chloride                                                                           Product          m.p. °C.                            ______________________________________                                        20   4-fluorobenzoyl                                                                            4-fluoro-N--[2-(1H--                                                                           121-123                                         chloride     imidazol-1-yl)ethyl]-                                                         benzamide                                                   21   3,4-dichloroben-                                                                           3,4-dichloro-N--[2-(1H--                                                                       137-140                                         zoyl chloride                                                                              imidazol-1-yl)ethyl]-                                                         benzamide                                                   ______________________________________                                    

When the procedure of Example 1 is carried out using 4-chlorobenzoylchloride or 4-bromobenzoyl chloride and the appropriate imidazolederivative, the products of Examples 22-25 were obtained as set forth inTable V below.

                  TABLE V                                                         ______________________________________                                        Ex.  Imidazole Derivative                                                                           Product       m.p. °C.                           ______________________________________                                        22   2,4-dimethyl-1H--imida-                                                                        4-chloro-N--[3-(2,                                                                          oil                                            zole-1-propanamine di-                                                                         4-dimethyl-1H--imi-                                          hydrochloride    dazol-1-yl)propyl]-                                                           benzamide                                               23   2-phenyl-1H--imidazole-                                                                        4-bromo-N--[3-(2-                                                                           162-165                                        1-propanamine dihydro-                                                                         phenyl-1H--imida-                                            chloride         zol-1-yl)propyl]-                                                             benzamide                                               24   4-phenyl-1H--imidazole-                                                                        4-chloro-N--[3-(4-                                                                          119-120                                        1-propanamine    phenyl-1H--imida-                                                             zol-1-yl)propyl]-                                                             benzamide                                               25   4-phenyl-1H--imidazole-1-                                                                      4-bromo-N--[3-(4-                                                                           133-135                                        propanamine      phenyl-1H--imida-                                                             zol-1-yl)propyl]-                                                             benzamide                                               ______________________________________                                    

EXAMPLE 26 1H-Imidazole-1-propanamine Derivatives

A mixture of 16.4 g. of 4-methylimidazole and 25 ml. of acrylonitrilewas heated at reflux temperature for 4 hours and then concentrated toremove the volatile material. The residue was mixed with 200 ml. ofethanol, 100 ml. of ammonium hydroxide and 6 g. of Raney Nickel catalystand reduced in a Parr Hydrogentator under hydrogen pressure untilreduction was complete. The catalyst was removed by filtration and themother liquor was concentrated to remove the solvents. The residual oilwas 4-methyl-1H-imidazole-1-propanamine. By substituting the appropriateimidazole starting material in the above procedure, the followingintermediates were prepared: 2-methyl-1H-imidazole-1-propanamine,2-ethyl-1H-imidazole-1-propanamine,2,4-dimethyl-1H-imidazole-1-propanamine,2-phenyl-1H-imidazole-1-propanamine and4-phenyl-1H-imidazole-1-propanamine.

EXAMPLE 27 4-Chloro-N-[3-(2ethyl-1H-imidazol-1-yl)propyl]benzamide

A mixture of 2.3 g. of 2-ethyl-1H-imidazole-1-propanediamine, 15 ml. of2N sodium hydroxide and 150 ml. of methylene chloride was stirred atroom temperature and 4.0 ml. of 4-chlorobenzoyl chloride was added. Thereaction mixture was stirred for 18 hours, then methylene chloride and15 ml. of 1N sodium hydroxide were added and the layers were separated.The organic layer was washed with water, dried over magnesium sulfateand concentrated. The crystalline residue was washed onto a filter withether and melted at 120°-122° C.

EXAMPLE 28 N-[3-(1H-Imidazol-1-yl)propyl]benzamide

A mixture of 1.22 g. of benzoic acid, 1.62 g. of1,1'-carbonyldiimidazole and 30 ml. of tetrahydrofuran was stirred for 3hours, then 1.98 g. of 1H-imidazole-1-propanamine dihydrochloride wasadded. The reaction mixture was stirred for 18 hours, then heated atreflux for 5 hours, then diluted with 5 ml. of water and heated for anadditional 30 minutes. The mixture was concentrated to remove most ofthe solvent and to the residue was added chloroform and 35 ml. of 1Nsodium hydroxide. The layers were separated. The organic layer waswashed with water, dried over magnesium sulfate, concentrated anddiethyl ether was added, giving the desired product, m.p. 134°-136° C.

Following the procedure of this example and using the appropriatebenzoic acid derivative, the products of Examples 29-40 were obtained asset forth in Table VI below.

                  TABLE VI                                                        ______________________________________                                        Ex.  Benzoic Acid Product           m.p.°C.                            ______________________________________                                        29   4-methoxy-   N--[3-(1H--imidazol-1-yl)-                                                                      132-135                                        benzoic acid propyl]-4-methoxybenz-                                                        amide                                                       30   3,4,5-trimethoxy-                                                                          N--[3-(1H--imidazol-1-yl)-                                                                      155-158                                        benzoic acid propyl]-3,4,5-trimethoxy-                                                     benzamide                                                   31   4-n-butoxybenzoic                                                                          4- -n-butoxy-N--[3-(1H--imi-                                                                    82-84                                          acid         dazol-1-yl)propyl]benz-                                                       amide                                                       32   4-acetylbenzoic                                                                            4-acetyl-N--[3-(1H--imida-                                                                      132-134                                        acid         zol-1-yl)propyl]benzamide                                   33   4-acetylaminoben-                                                                          4-(acetylamino)-N--[3-(1H--                                                                     230-232                                        zoic acid    imidazol-1-yl)propyl]-                                                        benzamide                                                   34   4-methylthioben-                                                                           N--[3-(1H--imidazol-1-yl)-                                                                      132-134                                        zoic acid    propy]-4-(methylthio)-                                                        benzamide                                                   35   4-methylsulfonyl-                                                                          N--[3-(1H--imidazol-1-yl)-                                                                      174-176                                        benzoic acid propyl]-4-(methylsul-                                                         fonyl)benzamide                                             36   4-iodobenzoic acid                                                                         N--[3-(1H--imidazol-                                                                            156-159                                                     1-yl)propyl]-4-                                                               iodobenzamide                                               37   4-phenyl-    N--[3-(1H--imidazol-                                                                            138-140                                        benzoic acid 1-yl)propyl(1.                                                                1'-biphenyl)-4-car-                                                           boxamide                                                    38   4-benzoyl-   4-benzoyl-N--[3-(1H--                                                                           107-109                                        benzoic acid imidazol-1-yl)pro-                                                            pyl]benzamide                                               39   4-dimethylamino-                                                                           N--[3-(1H--imidazol-                                                                            133-135                                        benzoic acid 1-yl)propyl]-4-(di-                                                           methylamino)benz-                                                             amide                                                       40   2-bromobenzoic                                                                             N--[3-(1H--imidazol-                                                                            95-98                                          acid         1-yl)-propyl]-2-                                                              bromobenzamide                                              ______________________________________                                    

EXAMPLES 41-45 SubstitutedN-[3-(2-methyl-1H-imidazol-1-yl)propyl]benzamides

By following the procedure of Example 27, the reaction of theappropriate benzoyl halide with 2-methyl-1H-imidazole-1-propanamineprovides the compounds set forth in Table VII below.

                  TABLE VII                                                       ______________________________________                                        Ex.    Benzoylhalide                                                                              Product       m.p.°C.                              ______________________________________                                        41     4-chlorobenzoyl                                                                            4-chloro-N--[3-(2-                                                                          142-144                                            chloride     methyl-1H--imida-                                                             zol-1-yl)propyl]-                                                             benzamide                                                 42     3-chlorobenzoyl                                                                            3-chloro-N--[3-(2-                                                                          130-132                                            chloride     methyl-1H--imida-                                                             zol-1-yl)propyl]-                                                             benzamide                                                 43     4-bromobenzoyl                                                                             4-bromo-N--[3-(2-                                                                           154-156                                            chloride     methyl-1H--imida-                                                             zol-1-yl)-propyl]-                                                            benzamide                                                 44     3,4-dichloroben-                                                                           3,4-dichloro-N--[3-                                                                         135-138                                            zoyl chloride                                                                              (2-methyl-1H--im-                                                             idazol-1-yl)-pro-                                                             pyl]benzamide                                             45     4-trifluoro- 4-trifluoromethyl-                                                                          124-126                                            methyl benzoyl                                                                             N--[3-(2-methyl-                                                 chloride     1H--imidazol-1-yl)-                                                           propy]benzamide                                           ______________________________________                                    

EXAMPLES 46-55 Substituted N-[3-(4-methyl-1H-imidazol-1-yl)propyl]amides

By following the procedure of Example 27, the reaction of theappropriate acid halide with 4-methyl-1H-imidazole-1-propanamineprovides the compounds of Table VIII.

                  TABLE VIII                                                      ______________________________________                                        Ex.  Acid halide   Product          m.p.°C.                            ______________________________________                                        46   3-chlorobenzoyl                                                                             3-chloro-N--[3-(4-                                                                             109-111                                        chloride      methyl-1H--imidazol-                                                          1-yl)propyl]benzamide                                      47   4-chlorobenzoyl                                                                             4-chloro-N--[3-(4-                                                                             126-130                                        chloride      methyl-1H--imidazol-l-                                                        yl)propyl]benzamide                                        48   3-bromobenzoyl                                                                              3-bromo-N--[3-(4-methyl-                                                                       108-112                                        chloride      1H--imidazol-1-yl)pro-                                                        pyl]benzamide                                              49   4-bromobenzoyl                                                                              4-bromo-N--[3-(4-methyl-                                                                       125-127                                        chloride      1H--imidazol-1-yl)pro-                                                        pyl]benzamide                                              50   4-iodobenzoyl 4-iodo-N--[3-(4-meth-                                                                          124-131                                        chloride      yl-1H--imidazol-1-                                                            yl)propyl]benzamide                                        51   3,4-dichlorobenzoyl                                                                         3,4-dichoro-N--[3-(4-                                                                          127-132                                        chloride      methyl-1H--imidazol-                                                          1-yl)propyl]benzamide                                      52   4-trifluoromethyl-                                                                          4-trifluoromethyl-N--                                                                          120-126                                        benzoyl chloride                                                                            [3-(4-methyl-1H--im-                                                          idazol-1-yl)propyl]-                                                          benzamide                                                  53   4-methylphenyl-                                                                             4-methyl-N--[3-(4-meth-                                                                        89-91                                          acetyl chloride                                                                             yl-1H--imidazol-1-yl)-                                                        propyl]phenylacetamide                                     54   2-phenylbenzoyl                                                                             2-phenyl-N--[3-(4-meth-                                                                        60 dec.                                        chloride      yl-1H--imidazol-1-yl)-                                                        propyl]benzamide fu-                                                          marate                                                     55   1-naphthoyl   N--[3-(4-methyl-1H--                                                                           110-123                                        chloride      imidazol-1-yl)pro-                                                            pyl]naphthalene-1-                                                            carboxamide                                                ______________________________________                                    

EXAMPLE 56 2-[4-(1H-Imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione

A mixture of 0.2 mol. of N-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione,0.22 mol. of sodium imidazole and 300 ml. of dimethylformamide wasstirred at 100° C. for 8 hours and then concentrated to remove thedimethylformamide. The residue was boiled with 500 ml. of toluene andthe insoluble material was removed by filtration. The toluene layer wasconcentrated to remove the solvent and the residue was further purifiedby HPLC using ethyl acetate and a silica gel column. The desired productmelted at 75°-77° C. Addition of ethanolic hydrogen chloride resulted inthe hydrochloride salt, mp. 200°-203° C.

When the above procedure is used to react sodium imidazole with theappropriate 2-(ω-bromoalkyl)-1H-isoindole-1,3(2H)-dione, the compoundsof Table IX were obtained.

                  TABLE IX                                                        ______________________________________                                        Ex.   Product                  m.p. °C.                                ______________________________________                                        57    2-[5-(1H--imidazol-1-yl)pentyl]-1H--isoin-                                                             194-197                                              dole-1,3(2H)--dione hydrochloride                                       58    2-[6-(1H--imidazol-1-yl)hexyl]-1H--isoin-                                                              83-87                                                dole-1,3(2H)--dione                                                     59    2-[7-(1H--imidazol-1-yl)heptyl]-1H--isoin-                                                             oil                                                  dole-1,3(2H)--dione                                                     60    2-[8-(1H--imidazol-1-yl)octyl]-1H--isoin-                                                              43-45                                                dole-1,3(2H)--dione                                                     61    2-[9-(1H--imidazol-1-yl)nonyl]-1H--isoin-                                                              oil                                                  dole-1,3(2H)--dione                                                     62    2-[10-(1H--imidazol-1-yl)decyl]-1H--isoin-                                                             69-70                                                dole-1,3(2H)--dione                                                     ______________________________________                                    

EXAMPLE 63 1H-Imidazole-1-butanamine

A mixture of 0.2 mole of2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione, 0.22 mol. ofhydrazine hydrate and 400 ml. of ethanol was heated on the steam bathfor 3 hours and then treated with 400 ml. of 3N HCl and heated at refluxfor an additional 2 hours. The insoluble material was filtered off andthe mother liquor was concentrated to a low volume and again filtered.The remainder of the volatile material was distilled off and the residuewas treated with saturated potassium carbonate solution. The1H-imidazole-1-butanamine was extracted into methylene chloride andfurther purified by distillation on a Kugelrohr apparatus. In likemanner from the appropriate2-[ω-(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-dione were prepared1H-imidazole-1-pentanamine, 1H-imidazole-1-hexanamine,1H-imidazole-1-heptanamine and 1H-imidazole-1-octanamine.

EXAMPLE 64 3,4-Dichloro-N-[4-(1H-imidazol-1-yl)butyl]benzamide

A solution of 1.05 g. of 3,4-dichlorobenzoyl chloride in 25 ml. ofmethylene chloride was added to a stirred solution of 1.06 g. of1H-imidazole-1-butanamine dihydrochloride in 15 ml. of 1N sodiumhydroxide. The mixture was stirred for 18 hours, methylene chloride wasadded and the layers were separated. The organic layer was washed withwater, dried over magnesium sulfate and concentrated. The residue waswashed onto a filter with diethyl ether, giving the desired product,m.p. 86°-88° C.

Following the procedure of this example and using the appropriatebenzoyl chloride, the products of Examples 65-70 were obtained as setforth in Table X below.

                  TABLE X                                                         ______________________________________                                        Ex.  Benzoyl Chloride                                                                            Product          m.p. °C.                           ______________________________________                                        65   4-chlorobenzoyl                                                                             4-chloro-N--[4-(1H--imid-                                                                      70-72                                          chloride      azol-1-yl)butyl]benz-                                                         amide                                                      66   4-bromobenzoyl                                                                              4-bromo-N--[4-(1H--imid-                                                                       105-106                                        chloride      azol-1-yl)butyl]ben-                                                          amide                                                      67   4-iodobenzoyl 4-iodo-N--[4-(1H--imid-                                                                        153-155                                        chloride      azol-1-yl)butyl]benz-                                                         amide                                                      68   4-acetylbenzoyl                                                                             4-acetyl-N--[4-(1H--imid-                                                                      70-83                                          chloride      azol-1-yl)butyl]benz-                                                         amide                                                      69   4-trifluoromethyl-                                                                          4-trifluoromethyl-N--[4-                                                                       103-120                                        benzoyl chloride                                                                            (1H--imidazol-1-yl)butyl]-                                                    benzamide fumarate                                         70   1-naphthoyl   N--[4-(1H--imidazol-1-yl)-                                                                      97-100                                        chloride      butyl]-naphthalene-1-car-                                                     boxamide                                                   ______________________________________                                    

EXAMPLES 71-75 Substituted N-[w-(1H-imidazol-1-yl)alkyl]benzamides

The compounds set forth in Table XI below were prepared from theappropriate 1H-imidazole-1-alkanamine (Example 63) by reaction with4-chlorobenzoyl chloride, 4-bromobenzoyl chloride or4-trifluoromethylbenzoyl chloride by the procedure of Example 1 butusing the base instead of the hydrochloride salt.

                  TABLE XI                                                        ______________________________________                                        Ex.  Compound                  m.p.°C.                                 ______________________________________                                        71   4-chloro-N--[5-(1H--imidazol-1-yl)pentyl]-                                                              92-94                                               benzamide                                                                72   4-bromo-N--[5-(1H--imidazol-1-yl)pentyl]-                                                               104-106                                             benzamide                                                                73   4-chloro-N--[6-(1H--imidazol-1-yl)hexyl]-                                                               72-76                                               benzamide                                                                74   4-trifluoromethyl-N--[5-(1H--imidazol-1-yl)-                                                            76-78                                               pentyl]benzamide                                                         75   4-chloro-N--[8-(1H--imidazol-1-yl)octyl]-                                                               83-85                                               benzamide                                                                ______________________________________                                    

EXAMPLE 76 4-Bromo-N-[3-(4-phenyl-1H-imidazol-1-yl)propyl]benzamide

A mixture of 28.8 g. of 4-phenyl imidazole and 25 ml. of acrylonitrilewas heated at reflux temperature for 6 hours and then concentrated toremove the volatile material. The residue was mixed with 200 ml. ofethanol, 100 ml. of ammonium hydroxide and 6 g. of Raney Nickel catalystand reduced in a Parr hydrogenator under hydrogen pressure untilreduction was complete. The catalyst was removed by filtration and thefiltrate was concentrated to remove the solvents. The residual oil was4-phenyl-1H-imidazole-1-propanamine.

A mixture of 2.0 g. of 4-phenyl-1H-imidazole-1-propanamine, 50 ml. ofmethylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.2g. of 4-bromobenzoyl chloride was added. The mixture was stirred foreighteen hours, methylene chloride was added and the layers wereseparated. The organic layer was washed with water, dried over magnesiumsulfate and concentrated. The residue was washed onto a filter withether, giving the desired product, m.p. 132°-135° C.

EXAMPLE 77 4-Chloro-N-[3-(4-phenyl-1H-imidazol-1-yl)propyl]-benzamide

When 4-chlorobenzoyl chloride was substituted for the 4-bromobenzylchloride of Example 76, There was obtained the title compound, m.p.103°-105° C.

EXAMPLE 78 N-[3-(1H-Imidazol-1-yl)propyl]-2-phenoxyacetamide

A mixture of 2.28 g. of phenoxyacetic acid, 2.43 g. of1,1'-carbonyldiimidazole and 50 ml. of tetrahydrofuran was stirred atroom temperature for 2 hours, then 3.0 g. of 1H-imidazole-1-propanaminedihydrochloride was added. The reaction mixture was stirred for 18hours, then heated at reflux temperature for 5 hours, 5 ml. of water wasadded, the mixture was heated for 30 minutes and then concentrated toremove the tetrahydrofuran. The residue was treated with methylenechloride and 50 ml. of 1N sodium hydroxide and the layers separated. Theorganic layer was washed with water, dried over magnesium sulfate andconcentrated. The residue was washed onto a filter with ether, givingthe desired product, m.p. 91°-93° C.

Following the procedure of this example and using the appropriatephenoxyacetic acid derivatives, the products of Examples 79 and 80 wereobtained as set forth in Table XII below.

                  TABLE XII                                                       ______________________________________                                        Ex.  Phenoxy Acetic Acid                                                                          Product         m.p.°C.                            ______________________________________                                        79   4-chlorophenoxy-                                                                             2-(4-chlorophenoxy)-N--                                                                       116-119                                        acetic acid    [3-(1H--imidazol-1-yl)-                                                       propyl]acetamide                                          80   2,3-dichlorophenoxy-                                                                         2-(2,3-dichlorophenoxy)-                                                                      oil                                            acetic acid    N--[3-(1H--imidazol-1-                                                        yl)propyl]acetamide                                       ______________________________________                                    

EXAMPLE 81 4-Fluoro-N-[3-(1H-imidazol-1-yl)propyl]benzeneacetamide

A mixture of 1.54 g. of 4-fluorophenylacetic acid, 1.62 g. of1,1'-carbonyldiimidazole and 30 ml. of tetrahydrofuran was stirred for 2hours, then 1.98 g. of 1H-imidazole-1-propanamine dihydrochloride wasadded. Stirring was continued at room temperature for an additional 18hours, then at reflux temperature for 5 hours, 5 ml. of water was added,the mixture was heated for 30 minutes and then concentrated to removethe volatile material. The residue was diluted with methylene chlorideand 25 ml. of 1N sodium hydroxide and the layers separated. The organiclayer was washed with water, dried over magnesium sulfate andconcentrated, giving the desired product as a viscous oil.

EXAMPLE 82 N-[3-(1H-Imidazol-1-yl)propyl]-4-methylbenzeneacetamide

Following the procedure of Example 81, but using 4-methylphenylaceticacid, the desired product was obtained as an oil.

EXAMPLE 83 3-Chloro-N-[3-(1H-Imidazol-1-yl)propyl]benzeneacetamide

Following the procedure of Example 81, but using 3-chlorophenylaceticacid, the desired product may be obtained as an oil.

EXAMPLE 84 N-[3-(1H-imidazol-1-yl)propyl]diphenylacetamide

Following the procedure of Example 81, but using diphenylacetic acid,the desired product is obtained as crystals, m.p. 136°-138° C.

EXAMPLE 85 N-[3-(1H-Imidazol-1-yl)propyl]-α-oxo-benzeneacetamide

Following the procedure of Example 81, but using benzoylformic acid, thedesired product was obtained as an oil.

EXAMPLE 86 N-[3-(1H-Imidazol-1-yl)propyl]-α-oxo-benzeneacetamide,fumarate

A mixture of 1.3 g. ofN-[3-(1H-imidazol-1-yl)propyl]-α-oxo-benzeneacetamide, 10 ml. of ethanoland 0.6 g. of fumaric acid was warmed to solution and then diluted withether. The resulting crystals were collected by filtration, washed withether and dried in vacuo, giving the desired product, m.p. 95°-105° C.

Following the procedure of this example but using the indicated startingmaterials, the fumarate salt products of Examples 87-91 were obtained asset forth in Table XIII below.

                  TABLE XIII                                                      ______________________________________                                             Starting Material                                                        Ex.  Product of Ex.                                                                              Product         m.p.°C.                             ______________________________________                                        87   14            N--[3-(1H--imidazol-1-                                                                        90-95                                                         yl)propyl]-4-(1,1-di-                                                         methylethyl)benzamide,                                                        fumarate                                                   88   81            4-fluoro-N--[3-(1H--imi-                                                                      101-103                                                       dazol-1-yl)propyl]ben-                                                        zeneacetamide, fumarate                                    89   80            2-(2,3-dichlorophenoxy)-                                                                       99-102                                                       N--[3-(1H--imidazol-1-                                                        yl)propyl]acetamide,                                                          fumarate                                                   90   82            N--[3-(1H--imidazol-1-                                                                        79-81                                                         yl)propyl]-4-methyl-                                                          benzeneacetamide, hemi-                                                       fumarate                                                   91   83            3-chloro-N--[3-(1H--imi-                                                                      109-111                                                       dazol-1-yl)propyl]ben-                                                        zeneacetamide, fumarate                                    ______________________________________                                    

EXAMPLE 92 N-[3-(1H-Imidazol-1-yl)propyl]cinnamamide

A mixture of 2.22 g. of trans-cinnamic acid, 2.43 g, of1,1'-carbonyldiimidazole and 50 ml. of tetrahydrofuran was stirred for 2hours, then 1.7 ml. of 1H-imidazole-1-propanamine was added. Thereaction mixture was stirred for 18 hours, then 5 ml. of water wasadded, the mixture was heated for 30 minutes and then concentrated.Methylene chloride and 10 ml. of 1N sodium hydroxide were added and thenlayers were separated. The organic layer was washed with water, driedover magnesium sulfate and concentrated, giving the desired product as aviscous oil.

Following the procedure of this example but using the appropriatecinnamic acid, the products of Example 93-95 were obtained, as set forthin Table XIV below.

                  TABLE XIV                                                       ______________________________________                                        Ex.  Cinnamic Acid                                                                             Product            m.p.°C.                            ______________________________________                                        93   3-chloro-   3-chloro-N--[3-(1H--imida-                                                                        99-101                                        cinnamic acid                                                                             zol-1-yl)propyl]cinnama-                                                      mide                                                         94   3,4-dichloro-                                                                             3,4-dichloro-N--[3-(1H--                                                                         122-124                                        cinnamic acid                                                                             imidazol-1-yl)propyl]-                                                        cinnamamide                                                  95   4-chloro-   4-chloro-N--[3-(1H--imidazol-                                                                    151-153                                        cinnamic acid                                                                             1-yl)propyl]cinnamamide                                      ______________________________________                                    

EXAMPLE 96 3-Amino-N-[3-(1H-imidazol-1-yl)propyl]benzamide

A mixture of 2.35 g. of N-[3-(1H-imidazol-1-yl)propyl]-3-nitrobenzamide,0.5 g. of 10% palladium on carbon catalyst and 150 ml. of ethanol wasshaken under 45 lbs. of hydrogen in a Parr hydrogenator until thereaction was complete. The catalyst was removed by filtration and themother liquor concentrated. The crystalline residue was washed onto afilter with ether, giving the desired product, m.p. 88°-90° C.

EXAMPLE 97 2-Amino-N-[3-(1H-imidazol-1-yl)propyl]benzamide

A mixture of 2.5 ml. of 1H-imidazole-1-propanamine, 3.2 g. of isatoicanhydride, and 30 ml. of toluene was heated at 90°-100° C. for 45minutes and cooled. The precipitate which separated was collected byfiltration. The desired product melted at 107°-110° C.

Following the procedure of this example and using the appropriateisatoic anhydrides, the products of Examples 98-103, found in Table XV,were obtained.

                  TABLE XV                                                        ______________________________________                                        Ex.  Isatoic Anhydride                                                                          Product           m.p.°C.                            ______________________________________                                         98  N--methyl-isatoic                                                                          N--[3-(1H--imidazol-1-                                                                          140-143                                        anhydride    yl)propyl]-2-methyl-                                                          aminobenzamide                                               99  N--ethyl-isatoic                                                                           2-ethylamino-N--[3-(1H--                                                                        115-117                                        anhydride    imidazol-1-yl)propyl]-                                                        benzamide                                                   100  N--benzyl-isatoic                                                                          2-benzylamino-N--[3-(1H--                                                                       oil                                            anhydride    imidazol-1-yl)propyl]-                                                        benzamide                                                   101  5-chloro-isatoic                                                                           2-amino-5-chloro-N--[3-                                                                         155-157                                        anhydride    (1H--imidazol-1-yl)-                                                          propyl]benzamide                                            102  N--allyl-5-chloro-                                                                         2-Allylamino-5-chloro-                                                                          102-104                                        isatoic anhydride                                                                          N--[3-(1H--imidazol-1-                                                        yl)propyl]benzamide                                         103  5-chloro-7-methyl-                                                                         2-amino-5-chloro-3-                                                                             233-236                                        isatoic anhydride                                                                          methyl-N--[3-(1H--imi-                                                        dazol-1-yl)propyl]-                                                           benzamide dihydro-                                                            chloride salt                                               ______________________________________                                    

EXAMPLE 104 N-[3-(1H-imidazol-1-yl)propyl]benzenepropanamide

A mixture of 1.50 g. of 3-phenylpropionic acid, 1.62 g. of1,1'-carbonyldiimidazole, and 40 ml. of tetrahydrofuran was stirred for3 hours and 2.0 g. of 1H-imidazole-1-propanamine was added. The mixturewas stirred for 18 hours, 5 ml. of water was added, and the reactionmixture was heated at reflux temperature for 30 minutes. The mixture wasconcentrated and 10 ml. 1N sodium hydroxide and 100 ml. of methylenechloride were added. The layers were separated and the organic layer waswashed with water, dried over magnesium sulfate, and concentrated. Thedesired product was obtained as an oil, which was converted to thefumarate salt, m.p. 90°-92° C.

Following the procedure of this example and using the appropriate acids,the products of Examples 105-110, found in Table XVI, were obtained.

                  TABLE XVI                                                       ______________________________________                                        Ex.  Acid         Product           m.p.°C.                            ______________________________________                                        105  4-phenylbutyric                                                                            N--[3-(1H--imidazol-1-yl)                                                                       oil                                            acid         propyl]benzene-butan-                                                         amide                                                       106  3-phenylbutyric                                                                            N--[3-(1H--imidazol-1-yl)                                                                       oil                                            acid         propyl]-beta-methyl-                                                          benzenepropanamide                                          107  2-phenylbutyric                                                                            alpha-ethyl-N--[3-(1H--                                                                         oil                                            acid         imidazol-1-yl)propyl]-                                                        benzeneacetamide                                            108  1-phenyl-1-cy-                                                                             1-phenyl-N--[3-(1H--imi-                                                                        oil                                            clopropane car-                                                                            dazol-1-yl)-propyl]                                              boxylic acid cyclopropane carbox-                                                          amide                                                       109  trans-2-phenyl-                                                                            2-phenyl-N--[3-(1H--imi-                                                                        oil                                            propane-1-car-                                                                             dazol-1-yl)-propyl]                                              boxylic acid cyclopropane carbox-                                                          amide                                                       110  2-phenylcylco-                                                                             2-cyclopentyl-N--[3-(1H--                                                                       oil                                            pentane acetic                                                                             imidazol-1-yl)propyl]                                            acid         benzeneacetamide                                            ______________________________________                                    

EXAMPLE 111 N-Benzyl-N-[3-(1H-imidazol-1-yl)propyl]benzamide

A mixture of 4.58 g. of N-[3-(1H-imidazol-1-yl)propyl]benzamide, 40 ml.of dimethylformamide, and 0.96 g. of 50% sodium hydride in oil wasstirred for 2 hours and 2.62 g. of benzyl bromide was added. The mixturewas stirred for 24 hours, concentrated to remove the dimethyl formamide,diluted with water and methylene chloride, and the layers separated. Theorganic layer was washed with water, dried over magnesium sulfate, andconcentrated. The oil was twice washed with hexane and againconcentrated. The desired product was obtained as an oil.

EXAMPLE 112 N-Ethyl-N-[3-(1H-imidazol-1-yl)propyl]benzamide

The above compound is obtained when ethyl bromide is substituted forbenzyl bromide in the procedure of Example 111.

EXAMPLE 113 3-(1H-Imidazol-1-yl)-2-methylpropanamine

A mixture of 15.0 g. of imidazole and 25 ml. of methacrylonitrile washeated at reflux temperature for 18 hours and then concentrated toremove the volatile material. The residue was mixed with 150 ml. ofethanol, 75 ml. of ammonium hydroxide and 6 g. of Raney Nickel catalystand reduced in a Parr hydrogenator under hydrogen pressure untilreduction was complete. The catalyst was removed by filtration and themother liquor was concentrated to remove the solvents. The residual oilwas used in reactions without further purification.

EXAMPLES 114-117 SubstitutedN-[3-(1H-imidazol-1-yl)-2-methylpropyl]benzamides

By reaction with the benzoyl chlorides in Table XVII by the procedure ofExample 27, the products of Table XVII below were obtained.

                  TABLE XVII                                                      ______________________________________                                        Ex.  Benzoyl Chloride                                                                             Product        m.p.°C.                             ______________________________________                                        114  4-chlorobenzoyl                                                                              4-chloro-N--[3-(1H--                                                                         141-144                                         chloride       imidazol-1-yl)-2-                                                             methylpropyl]ben-                                                             zamide fumarate                                           115  3-chlorobenzoyl                                                                              3-chloro-N--[3-(1H--                                                                         glass                                           chloride       imidazol-1-yl)-2-                                                             methylpropyl]ben-                                                             zamide                                                    116  3,4-dichlorobenzoyl                                                                          3,4-dichloro-N--[3-                                                                          glass                                           chloride       (1H--imidazol-1-                                                              yl)-2-methylpro-                                                              pyl]benzamide                                             117  4-bromobenzoyl 4-bromo-N--[3-(1H--                                                                          141-144                                                        imidazol-1-yl)-2-                                                             methylpropyl]ben-                                                             zamide                                                    ______________________________________                                    

EXAMPLES 118-121 3-(1H-Imidazol-1-yl)butanamine

When crotononitrile is reacted with imidazole by the procedure ofExample 113, 3-(1H-imidazol-1-yl)butanamine is obtained as an oil. Byreaction of this diamine with the appropriate benzoyl chloride by theprocedure of Example 27, the products set forth in Table XVIII below areobtained.

                  TABLE XVIII                                                     ______________________________________                                        Ex.  Benzoyl chloride                                                                             Product        m.p.°C.                             ______________________________________                                        118  3-chlorobenzoyl chlo-                                                                        3-chloro-N--[3-(1H--                                                                         107-109                                         ride           imidazol-1-yl)-                                                               butyl]benzamide                                           119  3,4-dichlorobenzoyl                                                                          3,4-dichloro-N--[3-                                                                          159-161                                         chloride       (1H--imidazol-1-yl)-                                                          butyl]benzamide                                           120  4-bromobenzoyl 4-bromo-N--[3-(1H--                                                                          122-124                                         chloride       imidazol-1-yl)-                                                               butyl]benzamide                                           121  4-chlorobenzoyl                                                                              4-chloro-N--[3-(1H--                                                                         102-104                                         chloride       imidazol-1-yl)-                                                               butyl]benzamide                                           ______________________________________                                    

EXAMPLE 122 3-(1H-Imidazol-1-yl)-3-phenylpropanamine

A solution of 6.0 g. of 3-(1H-imidazol-1-yl)propiophenone in 100 ml. ofmethanol was stirred as 23.1 g. of ammonium acetate, and then 1.35 g. ofsodium cyanoborohydrate was added. After 6 days at room temperature, 60ml. of concentrated hydrochloric acid was added and the solvent wasdistilled off. The residue was treated with 65 ml. of 10N sodiumhydroxide, 25 g. of sodium chloride and 200 ml. of methylene chlorideand the layers were separated. The organic layer was washed with water,dried over magnesium sulfate, and concentrated to obtain the desiredproduct as a viscous oil, 5.4 g. When this was reacted with4-chlorobenzoyl chloride and 4-bromobenzoyl chloride by the procedure ofExample 27, the compounds set forth in Table XIX were obtained.

                  TABLE XIX                                                       ______________________________________                                        Ex.     Compounds             m.p.°C.                                  ______________________________________                                        123     4-chloro-N--[3-(1H--imidazol-1-yl)-1-                                                               160-162                                                 phenylpropyl]benzamide                                                124     4-bromo-N--[3-(1H--imidazol-1-yl)-1-                                                                158-163                                                 phenylpropyl]benzamide                                                ______________________________________                                    

EXAMPLE 125 N-[3-(1H-imidazol-1-yl)propyl]phthalamic acid

A mixture of 0.01 mole of phthalic anhydride, 0.01 mole of3-(1H-imidazol-1-yl)propanamine and 30 ml. of methylene chloride wasstirred at room temperature for 3 hours and concentrated. The residuewas recrystallized from ethanol whereby the desired product, m.p.160°-162° C., was obtained. By substituting 3-fluorophthalic anhydride,4,5-dichlorophthalic anhydride, and 4-methylphthalic anhydride for thephthalic anhydride of this example, the compounds set forth in Table XXbelow were obtained.

                  TABLE XX                                                        ______________________________________                                        Ex.    Compounds              m.p.°C.                                  ______________________________________                                        126    3-fluoro-N--[3-(1H--imidazol-1-yl)pro-                                                               160-162                                                pyl]phthalamic acid                                                    127    4-methyl-N--[3-(1H--imidazol-1-yl)pro-                                                               161-163                                                pyl]phthalamic acid                                                    128    4,5-dichloro-N--[3-(1H--imidazol-1-yl)-                                                              176-178                                                propyl]phthalamic acid                                                 ______________________________________                                    

EXAMPLE 129 2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione

A mixture of 0.01 mole of phthalic anhydride and 0.01 mole of1H-imidazol-1-butanamine was heated in an oil bath at 160° C. for onehour. The reaction mixture was cooled and the product was purified byHPLC using ethyl acetate and a silica gel column. The melting point was75°-77° C.

When 4-bromophthalic anhydride was reacted with the appropriate amine bythe procedure of Example 129, the following compounds were obtained.

                  TABLE XXI                                                       ______________________________________                                        Ex.  Compounds                 m.p.°C.                                 ______________________________________                                        130  4-bromo-2-[3-(1H--imidazol-1-yl)propyl]-                                                                oil                                                 1H--isoindole-1,3(2H)--dione                                             131  4-bromo-2-[4-(1H--imidazol-1-yl)butyl]-1H--                                                             110-112                                             isoindole-1,3(2H)--dione                                                 132  4-bromo-2-[3-(1H--imidazol-1-yl)butyl]-                                                                 oil                                                 1H--isoindole-1 3(2H)--dione                                             133  4-bromo-2-[5-(1H--imidazol-1-yl)pentyl]-                                                                102-104                                             1H--isoindole-1,3(2H)--dione                                             ______________________________________                                    

EXAMPLES 134-135 Substituted2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-diones

By reacting 1H-imidazol-1-butanamine with other phthalic anhydridederivatives by the procedure of Example 129, the following compoundswere obtained.

                  TABLE XXII                                                      ______________________________________                                        Ex.   Compounds                m.p.°C.                                 ______________________________________                                        134   4-chloro-2-[4-(1H--imidazol-1-yl)butyl]-                                                               80-83                                                1H--isoindole-1,3(2H)--dione                                            135   4,5-dichloro-2-[ 4-(1H--imidazol-1-yl)butyl] -                                                         105-108                                              1H--isoindole-1,3(2H)--dione                                            ______________________________________                                    

EXAMPLES 136-139 Substituted2-[3-(1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-diones

By reacting 1H-imidazle-1-propanamine with substituted phthalicanhydrides by the procedure of Example 129, the following compounds wereobtained.

                  TABLE XXII                                                      ______________________________________                                        Ex.  Compound                  m.p. °C.                                ______________________________________                                        136  4-methyl-2-[3-(1H--imidazol-1-yl)propyl]-                                                               83-85                                               1H--isoindole-1,3(2H)--dione                                             137  4-nitro-2-[3-(1H--imidazol-1-yl)propyl]-1H--                                                            141-143                                             isoindole-1,3(2H)--dione                                                 138  4,5-dichloro-2-[3-(1H--imidazol-1-yl)propyl]-                                                           145-152                                             1H--isoindole-1,3(2H)--dione                                             139  3-chloro-2-[3-(1H--imidazol-1-yl)propyl]-                                                               92-94                                               1H--isoindole-1,3(2H)--dione                                             ______________________________________                                    

EXAMPLE 1404-Amino-2-[3-(1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione

A mixture of 0.1 mole of4-nitro-2-[3-(1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione, 200ml. of ethanol, 0.1 mole of 12N hydrochloric acid and 1.0 g. of Pd/Ccatalyst was reduced in a Parr hydrogenator under an initial H₂ pressureof 45 pounds per square inch pressure. The catalyst was filtered off andthe solvent was removed to obtain the desired compound as thehydrochloride salt.

EXAMPLE 141 2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione

A mixture of 0.1 mole of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione and0.1 mole of the silver salt of imidazole were heated in 300 ml. ofdimethylformamide for 8 hours. The reaction mixture was concentrated toremove the solvent and the residue was boiled with 200 ml. of tolueneand filtered to remove the insoluble material. The toluene layer wasconcentrated and the desired product was purified by HPLC using ethylacetate and a silica gel column.

EXAMPLE 142 2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione

A mixture of 0.01 mole of phthalimide and 0.01 mole of1H-imidazol-1-butanamine was heated in an oil bath at 140° for 1 hour.The reaction mixture was cooled to obtain the desired product.

EXAMPLE 143 2-[4-(1H-imidazol-1-yl)butyl]-1H-isoindole-1,3(2H)-dione

A mixture of 0.02 mole of potassium phthalimide, 0.01 mole ofN-(4-bromobutyl)imidazole hydrobromide and 100 ml. of dimethyl formamidewas gradually heated to 80° C. and held at this temperature for 3 hours.The solvent was removed in vacuo and the residue was purified by HPLCusing ethyl acetate and a silica gel column.

EXAMPLE 144 4-Chloro-N-[4-(1H-imidazol-1-yl)-2-butynyl]benzamide

A mixture of 27.8 g. of N-(4-bromo-2-butynyl)phthalimide, 9.0 g. ofsodium imidazole and 150 ml. of dimethylformamide is heated at 80° C.for 3 hours and then concentrated to remove the solvent. The residue isextracted with 500 ml. of hot toluene and the toluene layer isconcentrated to a viscous oil which is further purified by HPLC,developed with ethyl acetate to obtain2-[4-(1H-imidazol-1-yl)-2-butynyl)]-1H-isoindole-1,3(2H)-dione, m.p.139°-141° C.

A mixture of 0.05 mole of2-[4-(1H-imidazol-1-yl)-2-butynyl)]-1H-isoindole-1,3(2H)-dione, 0.05mole of hydrazine hydrate and 100 ml. of ethanol was heated on a steambath for 3 hours and then treated with 100 ml. of 3N hydrochloric acidand heated at reflux temperature for an additional 2 hours. Theinsoluble material was filtered off and the mother liquor wasconcentrated to a low volume and again filtered. The remainder of thevolatile material was distilled off and the residue was treated withsaturated potassium carbonate solution. The4-(1H-imidazol-1-yl)-butynamine was extracted into methylene chlorideand isolated as an oil by concentration of this solution.

A mixture of 2.68 g. of 4-(1H-imidazol-1-yl)-butynamine, 20 ml. of 1Nsodium hydroxide and 75 ml. of methylene chloride was stirred and 2.6ml. of 4-chlorobenzoyl chloride was added. The mixture was stirred for18 hours, 5 ml. of 1N sodium hydroxide was added and the layers wereseparated. The organic layer was washed with water, dried over magnesiumsulfate and concentrated to obtain the desired compound.

EXAMPLE 1454,5-Dichloro-2-[3-(4-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione

A mixture of 4.34 g. of 4,5-dichlorophthalic anhydride and 2.78 g. of3-(4-methyl-1H-imidazol-1-yl)propanamine was heated in an oil bath at165° C. for 40 minutes. The mixture was then boiled with 100 ml. tolueneand the toluene layer was allowed to cool to room temperature and thenfiltered from the insoluble material. The toluene layer was concentratedto remove the solvent and the crystalline residue was recrystallizedfrom ethyl acetate to obtain the desired compound, m.p. 147°-151° C.

EXAMPLE 146 4-Chloro-N-[4-(1H-imidazol-1-yl)-2-butenyl]-benzamidecarboxamide

A mixture of 100 g. of 1.4-dichlorobutene, 74 g. of potassiumphthalimide and 1500 ml. of dimethylformamide was stirred at roomtemperature for 24 hours. The reaction mixture was concentrated toremove the solvent and residue taken up with 2000 ml. of boiling hexaneand again concentrated. The residue was dissolved in methylene chloride,washed with water, dried over magnesium sulfate and concentrated toobtain 46 g. of N-(4-chloro-2-butenyl)isoindole-1,3(2H)-dione, m.p.79°-81° C.

A mixture of 23.5 g. of N-(4-chloro-2-butenyl)-isoindole-1,3(2H)-dione,11.0 g. of sodium imidazol and 200 ml. of dimethyl formamide was heatedon the steam bath for 18 hours and concentrated to remove the solvent;the residue was taken up in methylene chloride, washed with water, driedwith magnesium sulfate and again concentrated. The residue was dissolvedin hot ethylacetate and allowed to cool andN-[4-(1H-imidazol-1-yl)-2-butenyl]isoindole-1,3-(2H)-dione, m.p.106°-108° C., was obtained.

A mixture of 26.8 g. ofN-[4-(1H-imidazol-1-yl)-2-butenyl]isoindole-1,3-(2H)-dione, 4.85 ml ofhydrazine hydrate and 250 ml. of ethanol was heated at refluxtemperature for 6 hours. The mixture was cooled and 225 ml. of 3Nhydrochloric acid was added and the mixture was again heated at refluxtemperature for 3 hours. The precipitate was filtered off and the motherliquor was concentrated once more and then treated with saturatedpotassium carbonate solution. Extraction with methylene chlorideresulted in 4-(1H-imidizol-1-yl)-2-butenamine, obtained as an oil.

A solution of 1.65 g. of 4-(1H-imidazol-1-yl)-2-butenamine, 60 ml. ofmethylene chloride and 12 ml. of 1N sodium hydroxide was stirred and 1.6ml. of 4-chlorobenzoylchloride was added. The reaction mixture wasstirred for 18 hours, 40 ml. of methylene chloride and 5 ml. of 1Nsodium hydroxide was added and the layers were separated. The organiclayer was washed with water, dried over magnesium sulfate andconcentrated and the desired compound was obtained, m.p. 124°-126° C.

We claim:
 1. A compound selected from the group consisting of those ofthe formula: ##STR17## wherein A is a divalent moiety of the formulae:##STR18## wherein n is an integer from 2 to 8, inclusive, ARYL is1-naphthyl, 2-naphthyl, diphenylmethyl, 9-fluorenyl or a moiety of theformula: ##STR19## wherein R₁, R₂ and R₃ are each hydrogen, halogen,trifluoromethyl, cyano, carboxy, amino, alkyl(C₁ -C₄), alkoxy(C₁ -C₄),benzylamino, allylamino, alkyl(C₁ -C₃)amino, dialkyl(C₁ -C₃)amino,alkyl(C₁ -C₃)thio, alkyl(C₁ -C₃)sulfonyl, acetyl, acetylamino, phenyl orbenzoyl, Q is a divalent moiety of the formulae: ##STR20## wherein m iszero, 1, 2 or 3, R₄ is hydrogen, alkyl(C₁ -C₃) or benzyl, and R₅ and R₆are each hydrogen, alkyl(C₁ -C₃) or phenyl; and the pharmacologicallyacceptable acid-addition salts thereof.
 2. The compound according toclaim 1; 4-chloro-N-[3-(1H-imidazol-1-yl)propyl]benzamide.
 3. Thecompound according to claim 1;3-chloro-N-[3-(1H-imidazol-1-yl)propyl]benzamide.
 4. The compoundaccording to claim 1; 4-bromo-N-[3-(1H-imidazol-1-yl)propyl]benzamide.5. The compound according to claim 1;3,4-di-chloro-N-[4-(1H-imidazol-1-yl)butyl]benzamide.
 6. The compoundaccording to claim 1;4-bromo-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]benzamide.
 7. Thecompound according to claim 1;4-chloro-N-[3-(2-methyl-1H-imidazol-1-yl)propyl]benzamide.
 8. Thecompound according to claim 1;3-chloro-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]benzamide.
 9. Thecompound according to claim 1;4-chloro-N-[3-(2-methyl-1H-imidazol-1-yl)propyl]benzamide.
 10. Thecompound according to claim 1;3,4-di-chloro-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]benzamide.
 11. Thecompound according to claim 1;4-trifluoromethyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]benzamide. 12.The compound according to claim 1;4-trifluoromethyl-N-[4-(1H-imidazol-1-yl)butyl]benzamide.
 13. Thecompound according to claim 1;N-[3-(1H-imidazol-1-yl)propyl]-4-methylbenzeneacetamide hemifumarate.14. The compound according to claim 1;4-Bromo-N-[3-(2-phenyl-1H-imidazol-1-yl)propyl]benzamide fumarate.
 15. Athromboxane synthetase enzyme inhibiting composition of matter in dosageunit form comprising from about 10 mg. to about 700 mg. of a compound ofclaim 1 in association with a pharmaceutical carrier.